This project studies the role of the neuropeptide substance P (SP) in CNS regulation of blood pressure and possible abnormalities of this system in hypertension. Much evidence supports a role for SP as a neurotransmitter or neuromodulator of the baroreflex arc, the principal mechanism for instantaneous physiological regulation of blood pressure. SP apparently functions in this system at both afferent and efferent levels. SP appears to exert its neurotransmitter and/or neuromodulator effects in the CNS only after processing by enzymes which yield active N-terminal or C-terminal fragments. The N-terminal fragment SP(1-7) is produced by the endopeptidase 3.4.24.11 and appears to be a neurotransmitter for afferents from the carotid sinus and aortic arch which terminate in the nucleus tractus solitarius (NTS), while the C-terminal fragment SP(5-11) is produced by the post-proline cleaving enzyme and elevates blood pressure by stimulation of sympathetic outflow. SP(1-7) fulfills many of the criteria for being a neurotransmitter in the baroreflex arc. This project studies the role(s) of SP(1-7) in this system. Peptides related to SP(1-7) are synthesized in the search for antagonists and potent, long-acting agonists. These peptides are injected into the NTS to study their effect on blood pressure and functioning of the baroreflex. Antisera against the peptides and the processing enzymes will also be used. Other tachykinins and the neuropeptides calcitonin gene related peptide (CGRP) and neuropeptide Y (NPY) will also be studied. Interaction of SP and SP(1-7) with glutamate, which also fulfills many criteria for a neurotransmitter in this system, will be studied with specific glutamate agonists and antagonists. Other candidate neurotransmitter amino acids will also be studied.